Project Summary Malnutrition and nutrient deprivation are the single largest contributors to human mortality and profoundly impacts the severity and susceptibility to diseases. Amino acid and protein deprivation is the most common form of malnutrition in humans. We discovered that deprivation of essential amino acids has a profound impact on fat metabolism by repressing fat synthesis in the liver and inducing the loss of adipose tissue resulting in the complete depletion visceral fat stores. The response to deprivation of the essential amino acid leucine mimics a starvation response and is regulated by the amino acid sensor GCN2 eIF2 alpha kinase. More recently we discovered that GCN2 is required to repress both lipogenic and cholesterogenic gene expression during fasting. We propose to investigate the mechanism of whereby GCN2 represses the expression of the SREBPs, the key regulators of hepatic lipogenesis and cholesterogenesis. Studies to compare adaptation to fasting and deprivation of single essential amino acids in the liver will be conducted to determine shared and divergent regulatory pathways. In parallel, the regulation of loss of visceral fat, induced by depletion of essential amino acids, will be investigated to determine the role of GCN2 in controlling the oxidation of fatty acids during nutrient deprivation.